17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235, Apoptone) is an orally bioavailable synthetic analogue of 3β-androstanediol, that is active in rodent models of prostate and breast cancer, and is in Phase IIa clinical trials for the treatment of early- and late-stage prostate cancer. In preparation for clinical studies, nuclear hormone receptor and P450 interactions for HE3235 and major metabolites were characterized in vitro, and pharmacokinetics and metabolite profiles were studied in rodents, dogs, and monkeys. Four-week safety studies conducted in rats and dogs indicated a substantial margin of safety for clinical use, and no evidence of electrocardiographic or neurological effects, although anorexia, thrombocytopenia, and hypokalemia were identified as potentially dose-limiting toxicities at superpharmacological exposures. Pharmacokinetics and drug metabolism have been studied in prostate cancer patients.
Comparative pharmacotoxicity studies in rats were per formed to evaluate the response to r-metHuIL-2[ala-125] following 2 or 4 weeks of daily intravenous or sub cutaneous administration, as well as to evaluate pharmacokinetic and pharmacodynamic responses. Pharmacokinetic analysis indicated that r-metHuIL-2[ala- 125] showed high bioavailability and nonlinear concentra tion profiles. Pharmacodynamic responses to intravenous or subcutaneous dosing with r-metHuIL-2[ala-125], as measured by white blood cell counts, were comparable. Preclinical safety studies (6, 30, and 150 μg kg-1 day -1) indi cated that r-metHuIL-2[ala-125], whether given intra venously or subcutaneously, was associated with increased circulating and infiltrating levels of lympho cytes and eosinophils. Bone marrow lymphoid hyperpla sia and splenic extramedullary hematopoiesis were simi larly observed in each study. This pattern of effects was considered an exaggerated pharmacodynamic response to r-metHuIL-2[ala-125]. Of further note was a histopatholog ic finding described as hepatocyte single cell necrosis which was observed following both intravenous and sub cutaneous administration and was considered to be a toxic response to high doses of r-metHuIL-2[ala-125]. The no observable adverse effect level (NOAEL) for r-metHuIL- 2[ala-125] via intravenous administration was 6 μg kg -1 day-1, while that for subcutaneous administration was 30 μg kg-1 day-1. Data herein present a form of rHuIL-2 with pharmacokinetic and pharmacodynamic profiles that are similar when given by these two systemic routes. Pharmacotoxic data, based on NOAELs, suggest that sub cutaneous administration may be a preferred clinical route of administration.
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